Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.

BACKGROUND: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. OBJECTIVE: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. METHODS: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. RESULTS: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. CONCLUSIONS: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ). Methods: Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted. Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05. Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.

Distress, Depression, and the Effect of ZIP Code in Pancreaticobiliary Cancer Patients and Their Significant Others.

BACKGROUND: Distress screening of cancer patients is mandated by the American College of Surgeons Commission on Cancer. Clinical implementation remains limited, particularly in surgical oncology settings in individuals with pancreaticobiliary cancers. STUDY DESIGN: This study evaluated differences in mean distress scores based on the National Comprehensive Cancer Network Distress Thermometer & Problem List for patients with pancreaticobiliary cancers, benign pancreatic conditions, and for their significant others (SOs). The distress screening was conducted at the first office visit and postoperatively in a subset of those who had surgery. Distress Thermometer (DT) scores were dichotomized at ≤5 vs >5 and at ≥7 and correlated with Problem List items. The US ZIP Code database was used to correlate income range, percent poverty, and unemployment in the patient's self-identified ZIP code. Regression models were fitted to identify independent predictors of distress. RESULTS: A total of 547 patients and 184 SOs were evaluated. Thirty percent of patients had DT scores >5, with pancreatic adenocarcinoma patients reporting the highest levels of distress. SOs of pancreatic adenocarcinoma patients reported even greater distress than the patients themselves. As the number of pre-existing medical problems increased; so did DT scores. Distress correlated with physical and emotional problems and worry about insurance coverage and transportation. Higher income level predicted higher DT scores, although poverty predicted lower DT scores. Depression was present in 12% of the patients. Distress improved in those undergoing surgery. CONCLUSIONS: Distress and depression in pancreaticobiliary cancer patients and SOs are prevalent. The findings of this study have multiple actionable implications and require diagnosis, treatment, and referral to supportive care resources.

Using gamification to enhance clinical trial start-up activities.

Background: The Trial Innovation Network (TIN) is a collaborative initiative within the National Center for Advancing Translational Science (NCATS) Clinical and Translational Science Awards (CTSA) Program. To improve and innovate the conduct of clinical trials, it is exploring the uses of gamification to better engage the trial workforce and improve the efficiencies of trial activities. The gamification structures described in this article are part of a TIN website gamification toolkit, available online to the clinical trial scientific community. Methods: The game designers used existing electronic trial platforms to gamify the tasks required to meet trial start-up timelines to create friendly competitions. Key indicators and familiar metrics were mapped to scoreboards. Webinars were organized to share and applaud trial and game performance. Results: Game scores were significantly associated with an increase in achieving start-up milestones in activation, institutional review board (IRB) submission, and IRB approval times, indicating the probability of completing site activation faster by using games. Overall game enjoyment and feelings that the game did not apply too much pressure appeared to be an important moderator of performance in one trial but had little effect on performance in a second. Conclusion: This retrospective examination of available data from gaming experiences may be a first-of-kind use in clinical trials. There are signals that gaming may accelerate performance and increase enjoyment during the start-up phase of a trial. Isolating the effect of gamification on trial outcomes will depend on a larger sampling from future trials, using well-defined, hypothesis-driven statistical analysis plans.

Radiographic Assessment of Ankle Fracture Displacement: A Validation Study.

BACKGROUND: Ankle fracture displacement is an important outcome in clinical research examining the effectiveness of surgical and rehabilitation interventions. However, the assessment of displacement remains subjective without well-described or validated measurement methods. The aim of this study was to assess inter- and intrarater reliability of ankle fracture displacement radiographic measures and select measurement thresholds that differentiate displaced and acceptably reduced fractures. METHODS: Eight fellowship-trained orthopaedic surgeons evaluated a set of 26 postoperative ankle fracture radiographs on 2 occasions. Surgeons followed standardized instructions for making 5 measurements: coronal displacement (3) talar tilt (1), and sagittal displacement (1). Inter- and intraobserver interclass correlations were determined by random effects regression models. Logistic regression was used to determine the optimal sensitivity and specificity for the measurements with the highest correlation. RESULTS: Three of the 5 measures had excellent interobserver reliability (correlation coefficient > 0.75): (1) coronal plane distance between the lateral border of tibia and lateral border of talus, (2) coronal plane talar tilt, and (3) sagittal plane displacement. The threshold that best discriminated displaced from well-aligned fractures was 2 mm for coronal plane distance (sensitivity 82.1%, specificity 85.4%), 3 degrees for talar tilt (sensitivity 80.4%, specificity 82.2%), and 5 mm for sagittal plane distance (sensitivity 83.9%, specificity 84.9%). CONCLUSION: This study identified 3 reliable measures of ankle fracture displacement and determined optimal thresholds for discriminating between displaced and acceptably reduced fractures. These measurement criteria can be used for the design and conduct of clinical research studying the impact of surgical treatment and rehabilitation interventions.

One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability.

Importance: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited. Objective: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery. Design, Setting, and Participants: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022. Exposures: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care. Main Outcomes and Measures: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort. Results: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001). Conclusions and Relevance: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.

Bryostatin Placebo-Controlled Trials Indicate Cognitive Restoration Above Baseline for Advanced Alzheimer's Disease in the Absence of Memantine1.

BACKGROUND: In pre-clinical studies of Alzheimer's disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles. OBJECTIVE: Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment. METHODS: Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling. RESULTS: Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10-14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p = 0.005), and Study #202 = 4.2 SIB points above baseline (p = 0.016). An increased power (N = 95) "pooled analysis" showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p < 0.001) but not significant (NS) for the placebo patients. CONCLUSION: Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p < 0.001, placebo NS).

Sustainability of Intravenous Alteplase Administration via Telephone-Based Consult: Data from a US Health System.

OBJECTIVES: Telephone-based consults using remote imaging review and standardization of evaluation but without visualizing the patient are an alternative to video-telestroke consults but are less well-studied. We aim to demonstrate the safety and efficacy of telephone-based acute consults in which IV tPA was administered over nearly a decade within one health system. MATERIALS AND METHODS: Clinical characteristics and outcomes were compared between a community hospital (spoke; uses telephone-based consults) and the academic comprehensive stroke center (hub; uses oversight of on-site neurology trainees) from 2008-2017. In both institutions acute therapy decisions are made by the same stroke neurologists. RESULTS: 2518 acute ischemic stroke consults were evaluated at hub and 2049 at spoke. Of these, 191 patients received IV tPA at hub and 184 at spoke. Patients at hub were younger (median (IQR): 61 (51-74) vs 69 (56-81) years, p = 0.0021) but admission National Institutes of Health Stroke Scale (NIHSS) was similar. There were no differences between door-to-needle times (69 (56-101) vs 69 (51-92) minutes, p = 0.13), last known well-to-tPA times (157 (113-202) vs 144 (110-175) minutes, p = 0.053), and rates of overall intracranial hemorrhage (ICH) after tPA (n = 23 (13.5%) vs 31 (17.0%), p = 0.35). In multivariable analyses, hospital was not an independent predictor of ICH after tPA. CONCLUSIONS: In a large dataset over nearly a decade, assessment for IV tPA administration using telephone assessment along with imaging review and emergency department standardization resulted in similar safety and outcomes as in the presence of on-site stroke/neurology expertise. Future studies are needed to confirm these findings.

Early Advanced Weight-Bearing After Periarticular Fractures: A Randomized Trial Comparing Antigravity Treadmill Therapy Versus Standard of Care.

SUMMARY: In current clinical practice, weight-bearing is typically restricted for up to 12 weeks after definitive fixation of lower extremity periarticular fractures. However, muscle atrophy resulting from restricting weight-bearing has a deleterious effect on bone healing and overall limb function. Antigravity treadmill therapy may improve recovery by allowing patients to safely load the limb during therapy, thereby reducing the negative consequences of prolonged non-weight-bearing while avoiding complications associated with premature return to full weight-bearing. This article describes a multicenter randomized controlled trial comparing outcomes after a 10-week antigravity treadmill therapy program versus standard of care in adult patients with periarticular fractures of the knee and distal tibia. The primary hypothesis is that, compared with patients receiving standard of care, patients receiving antigravity treadmill therapy will report better function 6 months after definitive treatment.

Cognitive-Behavioral-Based Physical Therapy for Improving Recovery After Traumatic Orthopaedic Lower Extremity Injury (CBPT-Trauma).

SUMMARY: Physical and psychological impairment resulting from traumatic injuries is often significant and affects employment and functional independence. Extremity trauma has been shown to negatively affect long-term self-reported physical function, the ability to work, and participation in recreational activities and contributes to increased rates of anxiety and/or depression. High pain levels early in the recovery process and psychosocial factors play a prominent role in recovery after traumatic lower extremity injury. Cognitive-behavioral therapy pain programs have been shown to mitigate these effects. However, patient access issues related to financial and transportation constraints and the competing demands of treatment focused on the physical sequelae of traumatic injury limit patient participation in this treatment modality. This article describes a telephone-delivered cognitive-behavioral-based physical therapy (CBPT-Trauma) program and design of a multicenter trial to determine its effectiveness after lower extremity trauma. Three hundred twenty-five patients from 7 Level 1 trauma centers were randomized to CBPT-Trauma or an education program after hospital discharge. The primary hypothesis is that compared with patients who receive an education program, patients who receive the CBPT-Trauma program will have improved physical function, pain, and physical and mental health at 12 months after hospital discharge.

Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project.

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Intracranial Pressure and Cerebral Perfusion Pressure in Large Spontaneous Intracranial Hemorrhage and Impact of Minimally Invasive Surgery.

Introduction: We investigated the effect of hematoma volume reduction with minimally invasive surgery (MIS) on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with large spontaneous intracerebral hemorrhage (ICH). Methods: Post-hoc analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) study, a clinical trial with blinded outcome assessments. The primary outcome was the proportion of ICP readings ≥20 and 30 mmHg, and CPP readings <70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale >3) and mortality at 30 and 365 days. We assessed the relationship between proportion of high ICP and low CPP events and MIS using binomial generalized linear models, and outcomes using multiple logistic regression. Results: Of 499 patients enrolled in MISTIE III, 72 patients had guideline based ICP monitors placed, 34 in the MIS group and 38 in control (no surgery) group. Threshold ICP and CPP events ≥20/ <70 mmHg occurred in 31 (43.1%) and 52 (72.2%) patients respectively. On adjusted analyses, proportion of ICP readings ≥20 and 30 mmHg were significantly lower in the MIS group vs. control group [Odds Ratio (OR) 0.27, 95% Confidence Interval [CI] 0.11-0.63 (p = 0.002); OR = 0.18, 0.04-0.75, p = 0.02], respectively. Proportion of CPP readings <70 and 60 mm Hg were also significantly lower in MIS patients [OR 0.31, 95% CI 0.15-0.63 (p = 0.001); OR 0.30, 95% CI 0.11-0.83 (p = 0.02)], respectively. Higher proportions of CPP readings <70 and 60 mm were significantly associated with short term mortality (p = 0.04), and (p = 0.006), respectively. Long term mortality was significantly associated with higher proportion of time with ICP ≥ 20 (p = 0.04), ICP ≥ 30 (p = 0.04), and CPP <70 mmHg (p = 0.01). Conclusion: Our results are consistent with the hypothesis that surgical reduction of ICH volume decreases proportion of high ICP and low CPP events and that these variables are associated with short- and long-term mortality.

Post-Stroke Depression in Patients with Large Spontaneous Intracerebral Hemorrhage.

OBJECTIVES: To determine factors associated with post-stroke depression (PSD) and relationship between PSD and functional outcomes in spontaneous intracerebral hemorrhage (ICH) using prospective data from a large clinical trial. MATERIALS AND METHODS: MISTIE III, a randomized, multicenter, placebo-controlled trial, was conducted to determine if minimally invasive surgery with thrombolysis improves outcome compared to standard medical care. Our primary outcome was post-stroke depression at 180 days. Secondary outcomes were change in blinded assessment of modified Rankin Scale (mRS) from 30 to 180 days, and from 180 to 365 days. Logistic regression models were used to assess the relationship between PSD and outcomes. RESULTS: Among 379 survivors at day 180, 308 completed Center for Epidemiologic Studies Depression Scale, of which 111 (36%) were depressed. In the multivariable analysis, female sex (Adjusted Odds Ratio [AOR], 95% Confidence Interval [CI]: 1.93 [1.07-3.48]), Hispanic ethnicity (3.05 [1.19-7.85]), intraventricular hemorrhage (1.88 [1.02-3.45]), right-sided lesions (3.00 [1.43-6.29]), impaired mini mental state examination at day 30 (2.50 [1.13-5.54]), and not being at home at day 30 (3.17 [1.05-9.57]) were significantly associated with higher odds of PSD. Patients with PSD were significantly more likely to have unchanged or worsening mRS from day 30 to 180 (42.3% vs. 25.9%; p=0.004), but not from day 180 to 365. CONCLUSIONS: We report high burden of PSD in patients with large volume ICH. Impaired cognition and not living at home may be more important than physical limitations in predicting PSD. Increased screening of high-risk post-stroke patients for depression, especially females and Hispanics may be warranted.

Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage.

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

Intracerebral Hemorrhage Volume Reduction and Timing of Intervention Versus Functional Benefit and Survival in the MISTIE III and STICH Trials.

BACKGROUND: The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. OBJECTIVE: To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. METHODS: Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. RESULTS: End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. CONCLUSION: Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.

Refractory Hypocalcemia Following Stomach Intestinal Pylorus-Sparing Bariatric Surgery and Thyroidectomy: Successful Management With Creation of a Proximal Roux-en-Y Gastric Bypass.

Some forms of bariatric surgery make patients susceptible to calcium malabsorption, and the parathyroid hormone (PTH) axis is important for maintaining normocalcemia in these patients. Injury to the parathyroid glands due to anterior neck surgery commonly causes PTH axis disruption and can result in severe hypocalcemia in bariatric surgery patients. Herein, we present a case of a patient with a history of stomach intestinal pylorus-sparing bariatric surgery who developed refractory hypocalcemia requiring daily intravenous (IV) calcium 2 years after thyroidectomy. PTH levels were inappropriately normal during episodes of hypocalcemia, and urinary calcium level was <3.0 mg/dL following large oral doses of calcium, suggesting that both inadequate PTH response and malabsorption contributed to her severe hypocalcemia. In order to enhance calcium absorptive capacity while minimizing the risk of weight regain, she was surgically treated with a Roux-en-Y gastric bypass proximal to the prior operation. The surgery successfully improved blood calcium levels; the patient was successfully weaned from IV calcium and was able to maintain normocalcemia with oral supplements. We discuss the case in the context of available literature and provide our recommendations.

Randomised pilot trial of cash incentives for reducing paediatric asthmatic tobacco smoke exposures from maternal caregivers and members of their social network.

BACKGROUND: The primary aim was to evaluate the efficacy of financial incentives for reducing paediatric tobacco smoke exposures (TSEs) through motivating cigarette usage reduction among low-income maternal caregivers and members of their social network. DESIGN: Randomised control pilot trial over a 6-month study follow-up time period. The study was undertaken from May 2017 to -May 2018. Once monthly follow-up visits occurred over the 6-month study period. SETTING: Baltimore City, Maryland, USA. PARTICIPANTS: We grouped 135 participants into 45 triads (asthmatic child (2-12 years of age), maternal caregiver and social network member). Triads were assigned in a 1:1 allocation ratio. The maternal caregiver and social network members were active smokers and contributed to paediatric TSE. INTERVENTIONS: Triads were randomised to receive either usual care (TSE education and quitline referrals) or usual care plus financial incentives. Cash incentives up to $1000 were earned by caregivers and designated social network participants. Incentives for either caregivers or social network participants were provided contingent on their individual reduction of tobacco usage measured by biomarkers of tobacco usage. Study visits occurred once a month during the 6-month trial. MAIN OUTCOME MEASURES: The main outcome measure was mean change in monthly paediatric cotinine levels over 6 months of follow-up interval and was analysed on an intention-to-treat basis. RESULTS: The mean change in monthly child cotinine values was not significantly different in the intervention cohort over the 6-month follow-up period, compared with the control group (p=0.098, CI -0.16 to 1.89). Trends in child cotinine could not be ascribed to caregivers or social network members. Despite decreasing mean monthly cotinine values, neither the intervention cohort's caregivers (difference in slope (control-intervention)=3.30 ng/mL/month, CI -7.72 to 1.13, p=0.144) or paired social network members (difference in slope (control-intervention)=-1.59 ng/mL/month, CI -3.57 to 6.74, p=0.546) had significantly different cotinine levels than counterparts in the control group. CONCLUSIONS: Financial incentives directed at adult contributors to paediatric TSE did not decrease child cotinine levels. TRIAL REGISTRATION NUMBER: NCT03099811.

Linkage of Maternal Caregiver Smoking Behaviors on Environmental and Clinical Outcomes of Children with Asthma: A Post-Hoc Analysis of a Financial Incentive Trial Targeting Reduction in Pediatric Tobacco Smoke Exposures.

(1) Background: Monthly variability in smoking behaviors in caregivers of pediatric asthmatics yields questions of how much and when does smoking reduction result in improved environmental and clinical outcomes. (2) Methods: Post hoc analysis of data from a 6 month pilot randomized-control trial occurring from May 2017 to May 2018 in Baltimore City (MD, USA). The initial trial's primary intervention explored the utility of financial incentives in modifying caregiver smoking behaviors. Post hoc analyses examined all dyads independent of the initial trial's randomization status. All caregivers received pediatric tobacco smoke harm reduction education, in addition to monthly encouragement to access the state tobacco quitline for individual phone-based counseling and nicotine replacement therapy. Maternal caregivers who were active cigarette smokers and their linked asthmatic child (aged 2-12 years) were grouped into two classifications ("high" versus "low") based on the child and caregiver's cotinine levels. A "low" cotinine level was designated by at least a 25% reduction in cotinine levels during 3 months of the trial period; achieving ≤2 months of low cotinine levels defaulted to the "high" category. Twenty-seven dyads (caregivers and children) (total n = 54) were assigned to the "high" category, and eighteen dyads (caregivers and children) (total n = 36) were allocated to the "low" category. The primary outcome measure was the correlation of caregiver cotinine levels with pediatric cotinine values. Secondary outcomes included asthma control, in addition to caregiver anxiety and depression. (3) Results: Caregivers with 3 months of ≥25% decrease in cotinine levels had a significantly greater mean change in child cotinine levels (p = 0.018). "Low" caregiver cotinine levels did not significantly improve pediatric asthma control (OR 2.12 (95% CI: 0.62-7.25)). Caregiver anxiety and depression outcomes, measured by Patient Health Questionnaire (PHQ)-4 scores, was not significantly different based on cotinine categorization (p = 0.079); (4) Conclusion: Reduced pediatric cotinine levels were seen in caregivers who reduced their smoking for at least 3 months, but clinical outcome measures remained unchanged.